The objective of this study is to examine whether mutations in maternal and infant genes regulating folate metabolism are associated with an increased risk for the development of sporadic retinoblastoma. Environmental factors associated with poor living conditions may increase the risk of tumor formation, as the incidence of unilateral retinoblastoma is higher in several less affluent regions of the world. Mutations in the retinoblastoma gene, RB1 in germinal or dividing retinal cells result in tumor development. Most mutations occur at methylated cytosines, suggesting that abnormalities in methyl transfer may lead to mutagenesis. Folate, a regulator of methyl group transfer, is normally found in high concentrations in neural tissues and its deficiency can lead to mutagenesis through impaired methyl group transfer and pyrimidine synthesis. Risk for having a child with retinoblastoma is increased in women who do not take prenatal vitamin supplements and consume fewer folate-containing foods during pregnancy. The C677T and A1298C mutations in the methylene tetrahydrofolate reductase (MTHFR) gene and the A66G mutation in the methionine synthetase (MTRR) gene are common mutations in folate metabolizing enzymes genes which result in less functional enzymes. These act synergistically with low folate and co-balamin (B12) intake and increase the risk for neural tube defects. We hypothesize that decreased folate availability, because of poor intake, combined with less functional MTHFR and MTRR enzymes during key periods of retinal formation, in utero and in early infancy will lead to development of sporadic retinoblastoma. This molecular epidemiologic study proposes to use a case-control design, using questionnaires and blood samples, to examine two populations of mothers and children, one in central Mexico whose diet relies on foods not fortified with folate, and one in New York, where folate-fortified foods are widely consumed, in order to determine whether children with sporadic unilateral retinoblastoma and their mothers have an increased frequency of these MTHFR and MTRR mutations. The study will also examine whether the increased risk varies depending on folate intake, and levels of red blood cell and plasma folate, and plasma homocysteine. If our results are as anticipated, this project may lead to the development of new preventive strategies for those populations with an elevated incidence of sporadic retinoblastoma.